208547Orig1s000 - Food and Drug Administration · DOTATATE (~4800-fold safety factor based on the...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

208547Orig1s000

PHARMACOLOGY REVIEW(S)

Tertiary Pharmacology Review

By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IONDA: 208547Submission date: 7/1/15Drug: 68Ga dotatateSponsor: Advanced Accelerator Applications USA, Inc.Indication: PET imaging of neuroendocrine tumors

Reviewing Division: Division of Medical Imaging Products

Background Comments:The pharmacology/toxicology reviewer and team leader in the Division of Medical Imaging Products reviewed the nonclinical information for 68Ga dotatate and found it adequate to support approval from a pharmacology/toxicology perspective for the indication listed above.

Carcinogenicity studies have not been conducted with 68Ga dotatate. This is acceptable because the product is an imaging agent that is used acutely.

Developmental and reproductive toxicity studies have not been conducted with 68Ga dotatate. Radiopharmaceuticals such as 68Ga dotatate have the potential to cause fetal harm and the labeling will reflect that potential.

An appropriate established pharmacologic class for 68Ga dotatate would be “radioactive diagnostic agent.”

Conclusions:I concur with the Division pharmacology/toxicology recommendation that this NDA can be approved. I have provided labeling comments separately.

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Reference ID: 3937063

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---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

PAUL C BROWN05/26/2016


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DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION AND RESEARCH

PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION

Application number: 208547

Supporting document/s: 001

Applicant’s letter date: July 1, 2015

CDER stamp date: July 1, 2015

Product: Kit for the preparation of 68Ga-DOTA0-Tyr3-

Octreotate (aka 68Ga-DOTATATE)

Indication: 001

Applicant: Advanced Accelerator Applications USA, Inc.

New York, NY

Review Division: Medical Imaging

Reviewer: Ronald Honchel, Ph.D.

Supervisor/Team Leader: Adebayo Laniyonu, Ph.D.

Division Director: Libero Marzella, M.D., Ph.D.

Project Manager: Modupe Fagbami

Template Version: September 1, 2010

Disclaimer

Except as specifically identified, all data and information discussed below and necessary for approval of NDA 208547 are owned by Advanced Accelerator Applications USA, Inc. or are data for which Advanced Accelerator Applications USA, Inc. has obtained a written right of reference. Any information or data necessary for approval of NDA 208547 that Advanced Accelerator Applications USA, Inc. does not own or have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information described or referenced below from reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of NDA 208547.


NDA/BLA # 208547 Reviewer: Ronald Honchel, Ph.D.

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TABLE OF CONTENTS

1 Executive Summary…………………………………………..3

2 Drug Information………………………………………………6

3 Studies Submitted…………………………………………….8

4 Pharmacology…………………………………………………10

5 Pharmacokinetics/ADME……………………………………12

6 General Toxicology…………………………………………..15

7 Genetic Toxicology…………………………………………..26

8 Carcinogenicity……………………………………………….29

9 Reproductive an Developmental Toxicology……………29

10 Special Toxicology…………………………………………...29

11 Integrated Summary…………………………………………30

12 Appendix/Attachments………………………………………30



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1 Executive Summary

1.1 IntroductionOver 80 percent of neuroendocrine tumors (NETs) express somatostatin receptor 2. The Indium-111 labeled somatostatin analogue OctreoScan is currently approved for the SPECT localization of tumors expressing somatostatin receptor. DOTATATE is a somatostatin analogue with a peptide structure similar to OctreoScan. PET/CT imaging of NETs with 68Ga-DOTATATE has many advantages over SPECT imaging with 111In-OctreoScan that include significantly improved imagining resolution, more accurate quantification of radiotracer uptake, lower radiation dose and shorter imaging time. The Sponsor is seeking the approval of their kit for the preparation of 68Ga-DOTATATE as a radioactive diagnostic agent for NETs.


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1.2 Brief Discussion of Nonclinical FindingsMany nonclinical studies were performed using 177Lu-DOTATATE or 175Lu-DOTATATE. Since the only difference was the radiolabeled used, nonclinical data obtained using 177Lu-DOTATATE or 175Lu-DOTATATE is applicable for evaluating 68Ga-DOTATATE. The IC50 of DOTATATE for somatostatin sst2 receptor was determined in vitro to be 0.98 nM using membranes prepared from CA20948 tumors. There were no drug-related effects on Irwin scores or body temperatures at doses up to 20 mg/kg 175Lu-DOTATATE (~4800-fold safety factor based on the HED) in a rat neuro safety pharmacology study. 175Lu-DOTATATE induced increased mean, systolic, and diastolic arterial blood pressures with associated bradycardia at all dose levels (40-800 µg/kg) in a dog cardiovascular safety pharmacology study. Blood pressure was never increased, and heart rate never decreased, by more than 22% and changes were not clearly dose related. There were no drug-related effects on body temperatures and EKG. 175Lu-DOTATATE (100 µM) did not induce a significant reduction in hERG current in the hERG assay. 175Lu-DOTATATE induced a respiratory stimulatory effect at the 20 mg/kg dose in a rat respiratory safety pharmacology study. A less pronounced effect and fewer respiratory parameters were affected at the 5 mg/kg dose level. There were no drug-related effects on respiratory parameters observed at the 1.25 mg/kg dose level (~300-fold safety factor based on the HED). In a pivotal toxicity study, rats were administered via intravenous injection 0 (vehicle), 1.25, 5.0, or 20 mg/kg 175Lu-DOTATATE every 2 weeks for 42 days. An increased incidence in pancreatic acinar apoptosis was observed in the high dose treatment groups that had not completely reversed by the end of the recovery period. There were no other drug-related adverse effects observed in this study. The NOAEL was 5.0 mg/kg (~1200-fold safety factor based on the HED). In the other pivotal toxicity study, dogs were administered via intravenous injection 0 (vehicle), 80, 500, or 3200 µg/kg 175Lu-DOTATATE once every 2 weeks for 43 days. There were no drug-related adverse effects observed in this study (~2600-fold safety factor based on the HED). 175Lu-DOTATATE was not mutagenic in the Ames assay or the L5178Y TK+/- Mouse Lymphoma Cell assay.

1.3 Recommendations

1.3.1 ApprovabilityThe drug is approvable from a nonclinical perspective.1.3.2 Additional Non Clinical RecommendationsNone1.3.3 Labeling

Sponsor’s Proposed Version:

8.1 Pregnancy

Animal reproduction studies have not been conducted with


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Recommended Version:

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies have not been performed to evaluate the carcinogenic potential of 68Ga-DOTATATE. A very similar molecule (mixture 175Lu-DOTATATE/DOTATATE) was shown not to be mutagenic in the Ames assay and the L5178Y mouse lymphoma assay; however, any radiopharmaceutical including 68Ga-DOTATATE has the potential to be mutagenic. The effect of 68Ga-DOTATATE on fertility has not been evaluated.

2 Drug Information

2.1 DrugCAS Registry Number: 177943-89-4

Code Name: 68Ga-DOTA0-Tyr3-Octreotate (aka 68Ga-DOTATATE)

Molecular Formula/Molecular Weight: 1435.6/C65H99GaN14O19S2

Structure or Biochemical Description

Pharmacologic Class: Radioactive Diagnostic Agent

2.2 Relevant INDs, NDAs, BLAs and DMFsIND 77219 and PIND 122818 were cross-referenced.


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2.4 Comments on Novel ExcipientsThere were no novel excipients identified at the time of this review.

2.5 Comments on Impurities/Degradants of ConcernThere were no impurities or degradants of concern identified at the time of this review.

2.6 Proposed Clinical Population and Dosing RegimenDiagnostic for neuroendocrine tumors

NETs). The drug will be administered once via intravenous injection followed by PET/CT imaging. The mass dose to be administered is no more than 40 µg and the radiation dose is 0.054 mCi/kg.

2.7 Regulatory BackgroundAlthough not approved in the U.S., 68Ga-DOTATATE has been administered to hundreds of patients in Europe. The Sponsor cross-referenced IND 77219. Many of the nonclinical studies evaluated under IND 77219 were performed using 177Lu-DOTATATE or 175Lu-DOTATATE. Since the only difference is the radiolabel used, we previously agreed that nonclinical data obtained using 177Lu-DOTATATE or 175Lu-DOTATATE is applicable for evaluating 68Ga-DOTATATE.

3 Studies Submitted

3.1 Studies Reviewed

Pharmacology

Determination of binding affinity of somatostatin analogs using membranes prepared from CA20948 tumors.

Safety Pharmacology

175Lu-DOTATATE: Behavioral Irwin test and effect on body temperature following single intravenous administration in the rat. Study # 20100186PGRP

175Lu-DOTATATE: Evaluation of effects on blood pressure, heart rate, electrocardiogram and body temperature after single intravenous administration to conscious dogs. Study # 20100183PCCP

175Lu-DOTATATE: Evaluation of effects on hERG current in stably transfected HEK-293 cells. Study # 20100184PEHPPB

175Lu-DOTATATE: Evaluation of effects on respiration in the unrestrained conscious rat following single intravenous administration. Study # 20100185PCRP


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Pharmacokinetics/ADME

Biodistribution of 177Lu-DOTATATE in normal Sprague Dawley rats. Study # not stated.

Measurement of 175Lu-DOTATATE unbound fraction in dog, rat, and human plasma. Study # not stated.

68Ga-DOTATATE biodistribution in CD-1 healthy mice. Study # CEIP 039

68Ga-DOTATOC biodistribution/imaging in rat pancreatic AR42J cancer model in mice. Study # CEIP 045

Toxicology

175Lu-DOTATATE: 42-Day intravenous toxicity study in the rat by including recovery period and toxicokinetics. Study # 20100189TRP

175Lu-DOTATATE: 42-Day intravenous toxicity study in the dog by including recovery period and toxicokinetics. Study # 20100182TCP

Genetic Toxicology

175Lu-DOTATATE: Bacterial mutation assay. Study # 81900

175Lu-DOTATATE: Mutation in L5178Y Mouse Lymphoma Cells. Study # 81910

3.2 Studies Not Reviewed


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3.3 Previous Reviews ReferencedNone.

4 Pharmacology

4.1 Primary Pharmacology

Determination of binding affinity of somatostatin analogs using membranes prepared from CA20948 tumors.

The IC50s for various somatostatin analogues was evaluated in vitro using membranes prepared from CA20948 tumors. Results are shown in the Sponsor’s Table 1 below. DOTATATE exhibited the highest affinity of the ligand complexed derivatives. Cancer cell somatostatin receptor subtypes were not mentioned in the study report, but likely to be sst2.


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4.2 Secondary PharmacologySecondary pharmacology data was not submitted.

4.3 Safety Pharmacology175Lu-DOTATATE: Behavioral Irwin test and effect on body temperature following single intravenous administration in the rat. Study # 20100186PGRP

In this GLP study, male Wistar rats (n = 8/group) were scored by the Irwin assay and body temperatures collected. Rats were then administered via single intravenous injection 0 (vehicle), 1.25, 5.0, or 20 mg/kg 175Lu-DOTATATE. A positive control group was administered 0.3 mg/kg clonidine. Irwin scores and body temperatures were recorded at 5, 30 min, 1, 2, and 4 hours after dosing. Clonidine produced the expected sedative, neurovegetative, myorelaxant, and hypothermic effects. There were no drug-related effects on Irwin scores or body temperatures observed in this study (~4800-fold safety factor based on the HED).

175Lu-DOTATATE: Evaluation of effects on blood pressure, heart rate, electrocardiogram and body temperature after single intravenous administration to conscious dogs.

In part 1 of this GLP study, 8 telemeterized beagle dogs (4/sex) were administered via single bolus intravenous injection (2.5 mL/kg) 0 (vehicle), 80, 250, or 800 µg/kg 175Lu-DOTATATE in a cross-over design with a minimum of 3 days between doses. Blood pressure, heart rate, body temperature, and EKG were recorded. 175Lu-DOTATATE induced increased mean, systolic, and diastolic arterial blood pressures from 5 min through 6 hours after dosing with associated bradycardia. Blood pressure was never increased, and heart rate never decreased, by more than 22% and changes were not clearly dose related. There were no drug-related effects on body temperatures and EKG.

In part 2, the study was repeated with dogs administered via slow infusion (1.2 mL/min) intravenous injection of 0, 80, or 40 µg/kg 175Lu-DOTATATE in a cross-over design with a minimum of 3 days between doses. 175Lu-DOTATATE induced increased mean,



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systolic, and diastolic arterial blood pressures for up to 6 hours after dosing at the 80 µg/kg dose level and for up to 4 hours after dosing at the 40 µg/kg dose level with associated bradycardia.

175Lu-DOTATATE: Evaluation of effects on hERG current in stably transfected HEK-293 cells.

In this GLP study, HEK-293 cells stably transfected with hERG-1 cDNA were exposed to vehicle, then 100 µM 175Lu-DOTATATE, and finally 100nM of positive control E-4031 and hERG current was monitored. 175Lu-DOTATATE induced a maximum 19% decrease in hERG current compared to vehicle control values. E-4031 induced a further 91% inhibition of hERG current. Thus, 175Lu-DOTATATE was considered negative for the hERG assay.

175Lu-DOTATATE: Evaluation of effects on respiration in the unrestrained conscious rat following single intravenous administration.

In this GLP study, conscious male Wistar rats (n = 8/group) were administered via intravenous injection 0 (vehicle), 1.25, 5.0, or 20 mg/kg 175Lu-DOTATATE. A positive control group was administered 0.3 mg/kg carbamlycholine chloride. Respiratory rate, peak inspiratory and peak expiratory flows, inspiration and expiration times, airway resistance index, tidal volume and minute volume were then evaluated using whole body plethysmography for 4 hours following dosing. Carbamylcholine chloride produced the expected bronchoconstrictor effect that included increases in peak inspiratory and peak expiratory flows, tidal volume, minute volume, and airway resistance index and a decrease in expiration time. 175Lu-DOTATATE induced a respiratory stimulatory effect at the 20 mg/kg dose level that included increases in respiratory rate, peak inspiratory and peak expiratory flows, and minute volume, and decreases in inspiration time and expiration time. Less pronounced effects were observed at the 5 mg/kg dose level that included an increase in peak inspiratory flow and a decrease in inspiration time. There were no drug related effects observed at the 1.25 mg/kg dose level (~300-fold safety factor based on the HED).

5 Pharmacokinetics/ADME/Toxicokinetics

5.1 PK/ADMEBiodistribution of 177Lu-DOTATATE in normal Sprague Dawley rats.

Sprague Dawley rats (n = 24) were administered via intravenous injection 250 µCi 177Lu-DOTATATE and were euthanized at 5, 20, 15, 30, 60, 120, and 240 min after dosing. Blood, kidney, muscle and pancreas were removed and radioactivity levels were determined and the results shown in the Sponsor’s Table 1 below. Blood and muscle clearance of radioactivity was rapid. Kidney radioactivity levels were relatively high compared to blood levels. Although kidney radioactivity levels decreased between 10 min and 30 min after dosing, kidney radioactivity levels remained constant from 30



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min on. The high radioactivity levels observed in the kidney was expected due to renal clearance. Rat pancreas is known to have high levels of somatostatin-2 receptors and pancreas radioactivity remained relatively high throughout the study.

Measurement of 175Lu-DOTATATE unbound fraction in dog, rat, and human plasma.

Rat, dog or human plasma (diluted 1:1 with PBS) was spiked with 1000 or 300 ng/mL 175Lu-DOTATATE and dialysis was performed for 5 hr at 37ºC. Samples were then analyzed by LC-MS/MS. Results are summarized in the Sponsor’s Table 2 below. The highest fraction of unbound drug was observed in rat plasma dialyzed with 1000 ng/mL 175Lu-DOTATATE and human plasma dialyzed with 300 ng/mL 175Lu-DOTATATE. Otherwise, the unbound fraction was fairly constant at ~5-10%.

68Ga-DOTATATE biodistribution in CD-1 healthy mice.

Mice (n = 4/timepoint) were administered via intravenous injection 0.3 mCi 68Ga-DOTATATE and euthanized 30 min and 1, 2, and 4 hours after dosing. Blood and various organs were collected and radioactivity levels determine using a gamma-counter. Results are summarized in the Sponsor’s Table 1 below. Significant radioactivity was only seen in renal organs and the urine. This was expected due to renal being the primary route of excretion.



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68Ga-DOTATOC biodistribution/imaging in rat pancreatic AR42J cancer model in mice.

Female nude mice with implanted AR42J tumors were administered via intravenous injection 0.3 mCi 68Ga-DOTATOC (note – DOTATATE was not used) followed by whole body micro-PET imaging. The study conclusions were that 68Ga-DOTATOC showed a very good lesion diagnostic performance.

5.2 Toxicokinetics N/A



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6 General Toxicology

6.1 Single-Dose ToxicityThe single dose toxicity studies submitted by the Sponsor were performed using too few animals with too few toxicity parameters evaluated to provide useful interpretation of drug-induced toxicity.

6.2 Repeat-Dose ToxicityStudy title: 175Lu-DOTATATE: 42-Day intravenous toxicity study in the rat by including recovery period and toxicokinetics.

Study no.: 21000180TRPStudy report location: At the testing facility.

Conducting laboratory and location:

Date of study initiation: September 23, 2010GLP compliance: Yes

QA statement: YesDrug, lot #, and % purity: 175Lu-DOTATATE, FDOTA0501, % purity

not stated

Key Study FindingsRats were administered via intravenous injection 0 (vehicle), 1.25, 5.0, or 20 mg/kg 175Lu-DOTATATE every 2 weeks for 42 days on Days 1, 14, 28, and 42. An increased incidence in pancreatic acinar apoptosis was observed in high dose treatment groups that had not completely reversed by the end of the recovery period. There were no other drug-related adverse effects observed in this study. The NOAEL was 5.0 mg/kg (~1200-fold safety factor based on the HED).


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MethodsDoses: 0 (vehicle), 1.25, 5.0, or 20 mg/kg

Frequency of dosing: Every 2 weeks on Days 1, 14, 28, and 42 Route of administration: Intravenous

Dose volume: 5 mL/kgFormulation/Vehicle: Solution/Saline solution + 4.6% (v/v) acetate

bufferSpecies/Strain: Rat/Sprague Dawley

Number/Sex/Group: 10/sex/group main study; 5/sex/group recovery (high dose and vehicle control only)

Age: 7 weeks old at initiation of dosingWeight: Males 208 to 261 g; Females 163 to 215 g

Satellite groups: 6/sex/group for TK with blood samples collected predose, 5, 20, 60, 120, and 180 min post dose on Days 1 and 42.

Unique study design: An Irwin assay was performed and body temperatures were recorded. This is not the same behavioral study reported in the above safety pharmacology section.

Deviation from study protocol: There was only one minor deviation reported that did not affect the overall quality of the study.

Observations and Results

MortalityThere were no unscheduled deaths.Clinical SignsAnimals were observed at least once a day for clinical signs. There were no drug-related clinical signs noted.Body WeightsAnimals were weighed weekly. As seen in the Sponsor’s Table 2.3 below, a significant reduction of body weight gain was observed in treated males compared to controls during the second part of the treatment period that was considered possibly related to decreased feed consumption. The body weight gain in the high dose male group remained lower than the male vehicle control group during the recovery period.



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Feed ConsumptionFeed and water consumption was recorded weekly for each cage. Feed consumption tended to be decreased in male treatment groups relative to vehicle control, but feed consumption was measured by cage, thus the n was too low/group to do statistical evaluation. There were no obvious drug-related effects on water consumption.OphthalmoscopyOphthalmic examination was performed before dosing, on Day 42, and at the end of the recovery period. There were no drug-related ophthalmic findings noted.Hematology



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Blood samples for hematology parameter analyzes including PT and aPTT were collected on Day 43. There were no apparent drug-related effects on hematology parameters.Clinical ChemistryBlood samples for clinical chemistry parameter analyzes were collected on Day 43. There were no toxicologically significant drug-related changes in clinical chemistry parameters.UrinalysisUrine was collected from rats placed in metabolic cages over an approximately 16 hr period. Drug-related changes in urinalysis parameters were observed in treatment groups and included: 1) lower creatinine level in males dosed at 1250, 5000 and 20000 μg/kg (-14%, -15% and -28%, respectively) and females dosed at 20000 μg/kg (-25%); 2) lower sodium level in males dosed at 1250 and 5000 μg/kg (-41% and -56%, respectively); and 3) higher excreted volume in males and females dosed at 20000 μg/kg (+27% and +28%, respectively). No changes in urinalysis parameters were recorded during the reversibility period. The above changes were not severe enough to be considered adverse. There were no drug-related changes in urinalysis parameters in recovery groups. Gross PathologyMain study animals were euthanized on Day 43 and recovery animals were euthanized on Day 127 and full necropsies were performed. There were no drug-related macroscopic findings.Organ WeightsOrgan weights were collected on the tissues/organs shown in the Sponsor’s Table below. Lower absolute mean weights were observed for liver (12%-20% lower in treatment groups compared to control) and kidney (11% to 17% lower in treatment groups compared to control) in males. These decreases in organ weights were of questionable toxicological significance since the decreases were not dose related and there were no significant differences in relative liver and kidney weights. There were no other apparent drug-related changes in organ weights observed in this study.



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HistopathologyAdequate Battery: Yes.



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Peer Review: Not stated.

Histological Findings

An increased incidence in pancreatic acinar apoptosis was observed in the high dose treatment groups. Minimum to moderate pancreatic acinar apoptosis was reported in 16 of 20 high dose animals at the end of treatment period compared to minimal apoptosis being observed in 2 of 20 vehicle control animals. Minimum to moderate pancreatic acinar apoptosis was reported in 3 of 10 high dose animals at the end of the recovery period compared to 0 of 10 control animals. Special EvaluationThere were no clear drug-related effects on behavioral parameters or body temperatures.ToxicokineticsTK results are summarized in the Sponsor’s Tables 4 & 5 below. Systemic exposure (AUC) increased in a dose-related manner. There were no gender-related effects on exposure. The AUCs observed on Day 42 were similar to those observed on Day 1.



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Dosing Solution Analysis

Dosing formulations were analyzes via RP-HPLC with UV detection. The actual doses administered were within 10% of the nominal dose.

Study title: 175Lu-DOTATATE: 42-Day intravenous toxicity study in the dog by including recovery period and toxicokinetics.

Study no.: 20100182TCPStudy report location: At the testing facility.

Conducting laboratory and location:

Date of study initiation:GLP compliance: Yes

QA statement: YesDrug, lot #, and % purity: 175Lu-DOTATATE, Batch # FDOTA0501,

% purity not stated.

Key Study Findings


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Dogs were administered via intravenous injection 0 (vehicle), 80, 500, or 3200 µg/kg 175Lu-DOTATATE once every 2 weeks (Days 1, 15, 29, and 43) for 43 days. There were no drug-related adverse effects observed in this study (~2600-fold safety factor based on the HED).

MethodsDoses: 0 (vehicle), 80, 500, or 3200 µg/kg

Frequency of dosing: Single injections on Days 1, 15, 29, and 43Route of administration: Intravenous

Dose volume: 2.5 mL/kgFormulation/Vehicle: Solution/ Saline plus 1.4% (v/v) acetate buffer

Species/Strain: Dog/BeagleNumber/Sex/Group: 4/sex/group main study; 2/sex/group (high dose

and vehicle control only) for recovery groupsAge: 6-7 months old

Weight: Males 7.0 to 11.2 kg; Females 6.1-9.2 kgSatellite groups: None.

Unique study design: Systolic blood pressure was measured prior to dosing and Days 43, 71, 99, and 127.

Deviation from study protocol: There were only 2 minor deviations that did not affect the overall quality of the study.

Observations and Results

MortalityA low dose female was found moribund and died on Day 5. The probable cause of death was determined to be pulmonary disease unrelated to drug administration. There were no other unscheduled deaths observed in this study.Clinical SignsAnimals were observed once daily for clinical signs. Increased salivation, vocalization, or soft to liquid feces were observed during drug administration that was more marked in the highest dose group. These findings were transient and reversible and not severe enough to be considered adverse.Body WeightsAnimals were weighed weekly. There were no drug-related effects on body weights observed in this study.Feed ConsumptionFeed consumption was recorded daily. Feed consumption was slightly lower in the high dose groups that continued during the recovery period.OphthalmoscopyOphthalmic examinations were performed prior to dosing, on Day 43, and on Day 127. A mid-dose male showed inflammation of conjunctivae with sign of pain to light on Day



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23. This finding was not considered drug-related due to only observed in 1 animals and lack of dose response. There were no other ophthalmic findings observed in this study.ECGECGs were performed prior to dosing and Days 43, 71, 99, and 127. There were no drug-related effects on ECG parameters noted in this study.HematologyBlood samples for hematology parameter analyzes including PT and aPTT were collected prior to dosing and on Days 44, 72, 100, and 128. There were no significant drug-related effects on hematology parameters observed in this study.Clinical ChemistryBlood samples for clinical chemistry parameter analyzes were collected prior to dosing and on Days 44, 72, 100, and 128. There were no significant drug-related effects on clinical chemistry parameters observed in this study.UrinalysisAnimals were placed in metabolism cages and urine collected for a 16 hr period prior to the end of the treatment period and on Days 72, 100, and 128. Drug-related changes in urinalysis parameters are shown below. Urinary parameters returned to baseline during the recovery period.

Gross PathologyMain Study animals were euthanized on Day 44 and Recovery animals on Day 128 and full necropsies were performed. There were no drug-related macroscopic findings noted.Organ WeightsOrgan weights were collected on the tissues/organs shown in the Sponsor’s Table below. There were no drug-related changes in organ weights observed in this study.



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HistopathologyAdequate Battery: Yes



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Peer Review: Not stated.

Histological Findings

There was a slight treatment-related increase in the degree of pancreatic apoptosis observed in mid and high dose main study animals. Since this finding was also observed in 1 of 4 control males and 3 of control 4 females it was not considered to be adverse. There were no other drug-related macroscopic findings observed in this study.

Special EvaluationThe methodology was not stated, but the results section stated that body temperatures in treated animals were significantly increased for the groups and timepoints shown below compared to predose values. Body temperatures in the treated recovery group were similar to those recorded for the vehicle control recovery group.

There were no drug-related effects on systolic blood pressure noted in this study.ToxicokineticsBlood samples for TK analyzes were collected predose and 5, 20, 60, 120, and 180 min after dosing on Day 1 and Day 43. Mean TK results are summarized in the Sponsor’s Tables 4 & 5 below. Systemic exposure (AUC) increased in a dose-related manner. There were no gender-related effects on exposure. The AUCs observed on Day 43 were similar to those observed on Day 1.



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Dosing Solution Analysis

Dosing formulations were analyzes via RP-HPLC with UV detection. The actual doses administered were within 10% of the nominal dose.

7 Genetic Toxicology

7.1 In Vitro Reverse Mutation Assay in Bacterial Cells (Ames)Study title: 175Lu-DOTATATE: Bacterial mutation assay.

Study no.: 81900Study report location: Conducting Laboratory.

Conducting laboratory and location:Date of study initiation: November 22, 2010

GLP compliance: YesQA statement: Yes

Drug, lot #, and % purity: 175Lu-DOTATATE, Batch # LT101124A, % purity not stated

Key Study Findings175Lu-DOTATATE was not mutagenic in the Ames assay.


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MethodsStrains: S. typhimurium TA1535, TA1537, TA98 and

TA 100 and E.coli strain WP2 uvrA Concentrations in definitive study: 902, 285, 90.2, 28.5, and 9.02 µg/plate for

the toxicity test. 902, 451, 226, 113, and 56.4 µg/plate for Main assay I and II.

Basis of concentration selection: MFDNegative control: VehiclePositive control: See the Sponsor’s Table below

Formulation/Vehicle: Solution/acetate buffer pH 4.7Incubation & sampling time: For the toxicity study and Main Study I,

tester strain bacteria, test item, and S9 mix or phosphate buffer were added to molten overlay agar, vortexed and then poured on the minimal media agar plate. For Main Study II, bacterial suspension, tester strain bacteria, test item, and S9 mix or phosphate buffer were vortexed together and incubated for 30 min at 37ºC. This mixture was then added to molten overlay agar, vortexed and then poured on the minimal media agar plate. All plates were incubated for 72 hr at 37ºC. Afterwards, the number of revertant colonies were counted for each plate.



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Study ValidityTriplicate plates were used for each concentration in each study. No toxicity was observed in the absence or presence of S9 metabolism. No precipitation was observed in any study at any concentration. Mean plate counts for vehicle and positive control plates were within historical range values. These results indicate a valid study.Results175Lu-DOTATATE did not induce 2-fold increases in the number of revertant colonies at any dose level in the presence or absence of S9 mix in either Main Study.

7.2 In Vitro Assays in Mammalian CellsStudy title: 175Lu-DOTATATE: Mutation in L5178Y Mouse Lymphoma Cells.

Study no.: 81910Study report location: Conducting Laboratory

Conducting laboratory and location:Date of study initiation: November 22, 2010

GLP compliance: YesQA statement: Yes

Drug, lot #, and % purity: 175Lu-DOTATATE, Batch # LT101124A, % purity not stated

Key Study Findings


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MethodsCell line: L5178Y TK+/- Mouse Lymphoma Cells

Concentrations in definitive study: 395, 198, 98.8, 49.4, and 24.7 µg/mL without S9 mix and 395, 316, 253, 202 and 162 µg/mL with S9 mix.

Basis of concentration selection: MFD and no relevant toxicity or precipitation in a preliminary toxicity study at concentrations up to 395 µg/mL.

Negative control: VehiclePositive control: Methylmethanesulphonate (10 µg/mL)

without S9 mix and Benzo-a-pyrene (2.0 µg/mL) with S9 mix.

Formulation/Vehicle: Solution/Acetate bufferIncubation & sampling time: Cells and test article with and without S9

mix were incubated for 3 and 24 hr at 37ºC. Cells were washed in PBS, resuspended in fresh media and incubated at 37ºC in 5% CO2 for 2 days to allow for the expression of the mutant phenotype.

Study ValidityDuplicate cultures were prepared for each concentration. Relative total growth (RTG) was calculated and the mutation frequency was determined. Vehicle control values were within historical range. Positive controls induced marked increases in mutant frequencies. The results indicate a valid study.Results175Lu-DOTATATE did not induce an increase in the number of mutant colonies at any dose level in the presence or absence of S9 mix in either Main Study.

7.3 In Vivo Clastogenicity Assay in Rodent (Micronucleus Assay)

The only nonclinical genetic toxicology data submitted was for the Ames assay and the L5178Y TK+/- Mouse Lymphoma Cell assay.

8 CarcinogenicityCarcinogenicity data was not submitted.

9 Reproductive and Developmental ToxicologyReproductive and Developmental Toxicology data was not submitted.

10 Special Toxicology StudiesSpecial Toxicology study reports were not submitted.



30

11 Integrated Summary and Safety EvaluationThe Sponsor cross-referenced IND 77219. Many of the nonclinical studies evaluated under IND 77219 were performed using 177Lu-DOTATATE or 175Lu-DOTATATE. Since the only difference is the radiolabel used, nonclinical data obtained using 177Lu-DOTATATE or 175Lu-DOTATATE is applicable for evaluating 68Ga-DOTATATE. Many of the nonclinical study reports included in the submission were related to the oncology therapeutic indication or were not needed for microdosing and/or labeling. Such studies were not reviewed. The submission included 3 single-dose toxicity studies; however, these acute toxicity studies were not properly designed for evaluating drug-induced toxicity (too few animals used and/or too few parameters evaluated) with 2 of the studies clearly designed for dose-range finding. The repeat-dose toxicity studies were properly designed and were reviewed. There were no nonclinical concerns at the time of this review with the inactive ingredients, impurity, solvents, or degradants identified in the final drug product. Overall, the nonclinical data support that the NDA should be approved from a nonclinical perspective.

12 Appendix/Attachments

None.


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

RONALD HONCHEL12/04/2015

ADEBAYO A LANIYONU12/04/2015I agree with Dr. Honchel recommendation for the approval of this NDA application from a disciplineperspective. Dr. Honchel comments and recommendations on labeling are noted. Labelinglanguage consistent with the Pregnancy and Lactation Labeling Final Rule is being made at thereview team level.


208547Orig1s000 - Food and Drug Administration · DOTATATE (~4800-fold safety factor based on the...

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